Caloric restriction (CR) is the only nongenetic manipulation that significantly and consistently extends the life span. Although moderate CR has been shown to provide a variety of physiological benefits, few studies have included assessments of the effects of CR on the central nervous system. Recent evidence from our laboratory demonstrates that CR not only fails to ameliorate an age-related loss of synapses in sensorimotor cortex, it actually exacerbates that loss. Specifically, CR results in a 32 percent decrease in synapses in 29-month-old rats in comparison with age-matched, normally fed controls. Thus, despite the abundant physiological benefits that occur with CR, there is at least one striking and deleterious change within the brain. The proposed experiments will test the extent and time course of the CR-induced synaptic loss and attempt to elucidate the causal factors that produce it. A compelling candidate for mediating the effects of CR on synapses is the dramatic decline in plasma levels of IGF-I that occurs with moderate CR. Given that IGF-I crosses the blood brain barrier and is known to play a role in both synapse formation and maintenance, a CR-induced reduction in plasma and/or brain levels of IGF-I might well lead to a widespread loss of synapses. Moreover, since IGF-I also influences neurogenesis in the adult hippocampus, CR may lead to a decline in neuronal replacement as well. The proposed research will address the overall hypothesis that a CR-induced reduction in IGF-I results in a loss of synapses and a decline in neurogenesis within the adult brain. Several critical questions will be addressed: 1) Does the loss of synapses we have observed in sensorimotor cortex also occur elsewhere in the cortex and in the hippocampus? 2) What is the time course of CR-induced changes in IGF-I and synaptic density and, if present, in neurogenesis. 3) Will restoring CR animals to normal nutrition reverse CR- induced changes? 4) Will restoration of IGF-I levels in the brains of CR rats restore synapses and maintain neuronal proliferation. Given abundant evidence of beneficial effects of CR in other systems and the attractiveness of CR as a means for extending human life, a more complete understanding of the structural consequences of CR on the brain is essential.